INTRODUCTION — The Joint United Nations Programme on HIV and AIDS (UNAIDS) integrates the efforts of various United Nation organizations, including the World Health Organization (WHO), to control the global HIV epidemic, with the goal of eliminating HIV/AIDS as a public health threat by 2030 [1]. Expansive scale-up of services as part of UNAIDS initiatives since the beginning of the century has resulted in tremendous increases in antiretroviral access and coverage in resource-limited settings as well as associated reductions in new HIV cases, AIDS-related deaths, and overall mortality [2,3]. Despite these achievements, too many people with HIV worldwide are not receiving ART.
The impact of ART on HIV infection in resource-limited settings will be discussed here. The overall benefits of ART and information on the global epidemic are discussed elsewhere. (See "When to initiate antiretroviral therapy in persons with HIV" and "Global epidemiology of HIV infection".)
EPIDEMIOLOGY OF HIV — Of the estimated 38 million individuals with HIV worldwide in 2019, 25.6 million are in sub-Saharan Africa, where the overall prevalence is approximately 5 percent [4,5]. In some African countries, the prevalence exceeds 20 percent. More than half of the population with HIV in sub-Saharan Africa is women and children. HIV prevalence in Southeast Asia is substantially lower (0.6 percent), representing approximately four million people with HIV living in this under-resourced region. In Latin America and the Caribbean, infection rates vary by region, with estimated prevalences ranging from 0.5 to 2 percent. Markedly high rates of infection exist within certain risk groups, such as men who have sex with men, prisoners, commercial sex workers, and people who use injection drugs. The global epidemiology of HIV is discussed in detail elsewhere. (See "Global epidemiology of HIV infection", section on 'Worldwide statistics'.)
RECOMMENDATIONS FROM THE WORLD HEALTH ORGANIZATION
Initiation of ART — In 2015, the World Health Organization (WHO) revised longstanding guidance to withhold treatment until development of immunodeficiency and instead recommended initiation of antiretroviral therapy (ART) for all people with HIV, regardless of CD4 cell count or clinical stage [6]. Those with advanced HIV disease (clinical stage 3 or 4 disease (table 1)) or a CD4 cell count of <200 cells/microL are a priority for ART initiation. In general, initiation of ART should be offered within seven days of an HIV diagnosis or, for those who are ready to start therapy, on the day of diagnosis [7]. For people who have suspected or documented coinfection with tuberculosis (TB) or cryptococcal meningitis, ART initiation is deferred until those infections have been ruled out or treatment for those infections has been initiated. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)
The rationale for recommending ART initiation for all, even for those with high CD4 cell counts, includes:
●Benefit of ART at any CD4 cell count with regards to both AIDS- and non-AIDS-associated morbidity and mortality (see 'Effect of ART on mortality' below and 'Effect of ART on other comorbidities' below)
●Substantial reduction of sexual transmission of HIV to uninfected partners with the use of ART (see 'Impact of ART on transmission' below)
●Increasing availability of agents that are convenient, less toxic, and less costly
Similar reasons have been used to promote ART for all people with HIV in resource-rich settings. Mounting evidence has suggested that initiation of ART early during infection (even at CD4 cell counts higher than 500 cells/microL, which was the previously recommended threshold for initiation) is also beneficial in resource-limited settings. (See 'Optimal timing of ART' below.)
Of note, these recommendations apply only to individuals infected with HIV-1. The use of ART in people with HIV-2 infection is discussed in detail elsewhere. (See "Treatment of HIV-2 infection".)
Regimen selection — WHO guidelines specify a first-line regimen of dolutegravir in combination with a nucleoside reverse transcriptase inhibitor (NRTI) backbone for all populations with HIV, including females of childbearing potential and pregnant females [8]. Efavirenz at low dose (400 mg) in combination with a NRTI backbone is recommended as an alternative first-line regimen. In locations where the prevalence of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as efavirenz is ≥10 percent, NNRTI-based regimens as first-line ART should be avoided.
WHO guidance highlights several benefits of dolutegravir, including expected lower drug-drug interactions, decreased risk of development of drug resistance, and improved efficacy compared with efavirenz. As an example, in a randomized trial of over 1000 people with HIV in South Africa, there was a nonsignificant trend towards higher rates of viral suppression (<50 copies/mL) with two dolutegravir-based regimens compared with an efavirenz-based regimen (84 and 85 versus 79 percent) [9]. Similar findings were reported from a trial of over 600 people with HIV in Cameroon comparing a dolutegravir-based regimen to a regimen containing a lower dose of efavirenz (400 mg) [10].
The WHO also recommends dolutegravir in combination with an NRTI backbone during pregnancy and breastfeeding. Long-term nationwide surveillance in Botswana has observed comparable risk of neural tube defects with exposure to dolutegravir (0.11 percent, 95% CI 0.06-0.19) and other ART regimens (0.11 percent, 95% CI 0.07-0.16) [11], allying earlier concerns of increased risk [12]. Rates of stillbirth or prematurity are also similar [13] and viral suppression may be higher [14] for females receiving dolutegravir-containing ART.
Monitoring for and management of treatment failure — For most patients, treatment failure is defined as a persistent HIV viral load >1000 copies/mL for three months or more after at least six months of ART [6,15]. However, if a patient is on an NNRTI-based regimen, treatment failure is defined as a one-time HIV viral load >1000 copies/mL, given the known lower resistance threshold. Patients with treatment failure should be switched to an appropriate regimen.
If HIV RNA testing is not easily available, treatment failure should be indirectly assessed through CD4 cell count and clinical monitoring, with targeted viral load testing used as a confirmatory test when available. (See 'ART efficacy' below.)
Second-line regimens following treatment failure are typically chosen without knowledge of the presence of resistance mutations.
●In patients failing a dolutegravir-based regimen, the WHO recommends a boosted protease inhibitor plus at least two NRTIs as a second-line regimen.
●In patients failing a NNRTI-based regimen, the WHO recommends dolutegravir (or a boosted protease inhibitor if dolutegravir is contraindicated or unavailable) plus at least two NRTIs as a second-line regimen.
NRTIs used in the second-line regimen should be informed by the NRTIs used in the failing first-line regimen. As an example, if tenofovir and emtricitabine were the NRTIs used in the first-line regimen, the second-line NRTIs should be zidovudine and lamivudine. Despite concerns that failure on an NRTI-containing regimen would lead to cross-resistance to and thus decreased efficacy with other NRTI agents, NRTI-containing second-line regimens appear to maintain efficacy [16-20].
In an open-label randomized trial of 464 patients in sub-Saharan Africa with HIV who failed an NNRTI-based regimen with tenofovir and lamivudine, a switch to dolutegravir versus a protease inhibitor resulted in similar rates of HIV viral load suppression (<400 copies/mL) at 48 and 96 weeks, approximately 90 percent in each group [20,21]. As a second randomization, patients were assigned to either remain on tenofovir or switch to zidovudine, and both of these groups also experienced similar rates of viral load suppression (92 versus 90 percent). However, since NRTI mutations are common among patients failing NNRTI-based regimens, longer term follow-up is needed before recommending continuing the NRTI backbone of the failing regimen.
In resource-rich settings, genotypic testing is used to guide second-line therapy. However, genotypic testing is not readily accessible in many resource-limited settings and the WHO does not recommend routine genotype testing in patients failing first-line ART regimens. Although an unblinded, randomized trial of 840 patients in sub-Saharan Africa demonstrated that genotypic testing did not improve rates of viral load suppression at nine months in patients failing first-line NNRTI-based regimens, poor adherence and high number of patients switching to second-line therapy in both groups may have reduced the ability to detect a difference in outcome [22].
Prevention of coinfections — WHO guidelines recommend the following evaluation and preventive interventions at the time of HIV diagnosis and ART initiation (algorithm 1) [7,15]:
●For all people with HIV – Screen for clinical symptoms of active tuberculosis and test for latent tuberculosis infection, if such tests are available. Treat for latent tuberculosis with isoniazid in those who have unknown or positive tuberculin skin tests and are unlikely to have active tuberculosis. The duration depends on the regional prevalence of tuberculosis. Details on the evaluation and treatment of latent tuberculosis in people with HIV are discussed elsewhere. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)" and "Treatment of latent tuberculosis infection in nonpregnant adults with HIV infection".)
●Additionally, for people with HIV five years and older who have CD4 counts <350 cells/microL or WHO clinical stage 3 or 4 disease (table 1), for children with HIV younger than five years, and for people with HIV who live in a region where malaria and/or bacterial infections are common (regardless of CD4 cell count) – Administer trimethoprim-sulfamethoxazole prophylaxis.
WHO recommends continuing trimethoprim-sulfamethoxazole prophylaxis until the person is clinically stable on ART, with evidence of immune recovery and virologic suppression. However, indefinite prophylaxis regardless of HIV clinical status is recommended in regions where malaria and bacterial infection are common.
●Additionally, for adults and adolescents with HIV and CD4 cell count ≤100 cells/microL – Screen with a cryptococcal antigen test prior to ART initiation. For those with a positive test (or those without access to cryptococcal antigen testing) but without evidence of cryptococcal meningitis, preemptively treat with fluconazole. This approach can also be considered for people with CD4 counts between 100 and 200 cells/microL [23]. Antifungal therapy can be discontinued once the person is clinically stable on ART, has received antifungal therapy for at least one year, and has a sustained CD4 cell count ≥200 cells/microL or a sustained CD4 cell count ≥100 cells/microL with a suppressed viral load. Details on the evaluation for and prevention of cryptococcal infection in people with HIV are discussed elsewhere. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention".)
These recommendations are based on data demonstrating reduced morbidity and mortality with trimethoprim-sulfamethoxazole prophylaxis and with preemptive therapy of cryptococcal and latent tuberculosis infection. (See 'Impact of prophylaxis against coinfections' below.)
EFFECT OF ART ON MORTALITY
Treatment-naïve patients — Meta-analyses of antiretroviral therapy (ART) trials in resource-limited settings, along with subsequent larger cohort studies and a randomized trial, have demonstrated that treatment-induced viral suppression and immune recovery lead to improved clinical status and reduced mortality [24-28]. Reductions in mortality are evident even among people with advanced immunosuppression [26,29-31], and the magnitude of mortality reduction has been generally similar to that in resource-rich countries. One prospective cohort study in Uganda found that the life expectancy of 22,315 people with HIV receiving ART was comparable with the national average, despite the use of less potent and more toxic treatment regimens than those in use in resource-rich settings [26].
However, disproportionately high mortality has been observed among some people soon after ART initiation, especially among profoundly immunosuppressed persons [24,27,30,32-35]:
●Of more than 21,000 people who were enrolled into HIV care in Zambia, 71 percent of the total number of deaths (n = 1142) occurred within 90 days of starting ART, while the remaining 29 percent occurred after 90 days [33]. In a multivariable analysis, mortality was strongly associated with a low baseline CD4 cell count (range 50 to 199 cells/microL; adjusted hazard ratio [HR] 2.2; 95% CI 1.5-3.1).
●A meta-analysis of adults initiating ART in sub-Saharan Africa demonstrated that the highest mortality rates occurred among those adults with advanced AIDS; specifically, having a baseline CD4 count <50 cells/microL and World Health Organization (WHO) stage 4 disease was associated with twice the likelihood of death (summary HR, 2.2; 95% CI 1.5-3.2) (table 1) [34].
●In a separate meta-analysis of adults initiating ART in low- and middle-income countries, mortality rates ranged from 7 to 17 percent at one year after ART initiation. There was an increased risk of death with male gender, age greater than 40 years, low BMI, anemia, advanced clinical HIV disease, and low CD4 counts at initiation [36].
Poor ART responses are also related to advanced age [37], bone marrow suppression, low body weight, and malnutrition [33,38].
Because the highest mortality rates occur among those with severe immunosuppression, greater survival benefit may be attained with expanded availability of ART prior to the onset of advanced disease [26,39].
●In a cohort study of over 22,000 Ugandan adults enrolled in ART clinics, there was an association with lower mortality in people who initiated ART at higher CD4 counts after adjustment for sex, WHO disease stage, and year of ART initiation [27]. The relative risk of death was 0.75 (95% CI 0.65–0.88) in those with baseline CD4 counts between 50 and 99 cells/microL and 0.41 (95% CI 0.33–0.51) in those with baseline CD4 counts ≥250 cells/microL compared with adults who initiated ART at CD4 counts <50 cells/microL.
●Other observational data have also supported earlier initiation of ART in people with CD4 counts >200 cells/microL, not only in reducing mortality, but also in improving overall rates of treatment-induced viral suppression compared with deferred ART [40].
●Initiation of ART in people with CD4 counts ≤350 cells/microL has mortality benefit for all patients with HIV. In a randomized trial conducted in Haiti, 816 study participants with a baseline CD4 count between 200 and 350 cells/microL were randomly assigned to either "standard ART" or "early ART" [28]. "Standard ART" was initiated at the onset of clinical AIDS or a CD4 cell count <200 cells/microL, whereas "early ART" was initiated within two weeks of study enrollment. A significantly higher number of deaths occurred in the standard rather than in the early ART arm (ie, 23 versus 6 deaths; HR 4, 95% CI 1.6-9.8).
The mortality benefits of ART likely extend to individuals with CD4 cell counts >350 cells/microL through reduction in severe illnesses [41-43]. WHO guidelines for initiation of ART in resource-limited settings are discussed elsewhere. (See 'Recommendations from the World Health Organization' above.)
Long-term follow-up — Benefits of ART in resource-limited settings are retained during follow-up. In a multi-site longitudinal cohort with 29,175 people who initiated care, 19,967 people with HIV were followed for more than six months and 820 people were followed for more than four years (median follow-up time 1.6 years) [42]. Overall, mortality and loss to follow-up were low (3 percent and 9 percent, respectively). Immune reconstitution was substantial among those with advanced immunosuppression (395 cells/microL at five years from a median nadir of 114 cells/microL); the trajectory of CD4 cell gain on ART was greater among those who initiated treatment at higher CD4 counts.
In a separate study of people initiating ART at multiple South African clinical sites, mortality rates at two to four years post-ART initiation were 12-fold lower than mortality rates at three months after ART initiation [44]. An estimation of life-expectancy of people with HIV on ART in Uganda suggested that people engaged in care and on ART could live over 20 additional years, which is near normal for adults in the region; those who initiated ART at higher CD4 counts had longer life expectancy [26]. In a population cohort study of more than 101,000 individuals in rural KwaZulu-Natal, South Africa, after eight years of ART availability to the public (from 2003 to 2011), the average adult life expectancy increased by 11.3 years (49.2 years to 60.5 years) [45].
Gender differences in mortality — In resource-limited settings, men with HIV appear to have a higher risk of death than women despite ART [46-48]. In a retrospective study of 46,201 individuals with HIV in South Africa initiating ART between 2002 and 2009, the mortality rate was higher among men than women (8.5 versus 5.7 deaths per 100 person-years) [46]. Although men were older, had lower median CD4 cell counts, and were more likely to have advanced HIV (WHO stage III to IV) at ART initiation compared with women, a difference in mortality rate remained significant (adjusted HR 1.31, 95% CI 1.22-1.41) after adjusting for these and other variables. Men also had a higher rate of loss to follow-up than women, but even among those patients who achieved viral suppression to <400 copies/mL on ART, the risk of death remained higher for men. A proportion of the excess mortality was thought to reflect the HIV-unrelated mortality differences observed between men and women in resource-limited settings.
Second-line therapy — Second-line therapy is increasingly available for people with HIV in resource-limited communities who experience therapy-limiting toxicities or clinical failure, especially when due to the emergence of resistance to non-nucleoside reverse transcriptase inhibitor and NRTI agents. Outcomes data remain mixed regarding those who change to second-line regimens. A large observational multi-center cohort in Asia and Africa demonstrated high failure rates in addition to substantial morbidity and mortality after change to second-line therapy [49], but other cohort studies have reported virologic suppression rates of >70 percent on second-line regimens and demonstrated a beneficial effect of second-line therapy on mortality and immune reconstitution [50-53].
Failure of second-line regimens has been associated with ongoing poor adherence [52], and emergence of PI mutations remains rare [53,54]. (See 'Drug resistance' below.)
EFFECT OF ART ON OTHER COMORBIDITIES — A growing body of evidence demonstrates the benefit of antiretroviral therapy (ART) in specifically attenuating the effects of HIV on a variety of highly prevalent illnesses in developing countries, as discussed below.
Tuberculosis — Substantial additional morbidity and mortality from tuberculosis (TB) coinfection occurs in untreated people with HIV in resource-limited settings with evidence of a fivefold increased risk of active TB in patients with HIV [55]. This risk of TB increases with declining immunity. (See "Diagnosis of pulmonary tuberculosis in adults".)
People with HIV may have active pulmonary TB without clinical symptoms [55-57]. Furthermore, unsuspected TB is associated with higher rates of morbidity and mortality after initiation of ART compared with those without concomitant TB [58]. Given the high prevalence of coinfection in many resource-limited regions, intensified TB case finding with screening, regardless of symptoms, may help in case identification and in reducing early morbidity when initiating ART [56,59].
TB incidence — Widespread use of ART has been associated with a decreased incidence of tuberculosis (TB) and up to a 70 percent reduction in death among people with HIV coinfected with tuberculosis [28,60-63].
●In a treatment trial conducted in Haiti, 816 people with HIV were randomly assigned to early ART (two weeks after enrollment) or to standard ART (initiation of ART when CD4 counts declined to ≤200 cells/microL or for the onset of clinical AIDS) with isoniazid prophylaxis administered to all study participants. Early initiation of ART was associated with a twofold decline in TB incidence over a median follow-up of 21 months [28].
●Even among people with higher CD4 cell counts, ART reduces the incidence of TB. In a randomized trial from Ivory Coast of over 2000 people with HIV and CD4 cell counts <800 cells/microL, there was a lower rate of active tuberculosis among individuals who initiated ART at the time of enrollment compared with those who initiated ART once the World Health Organization (WHO) criteria were met, which evolved over the course of the trial (hazard ratio 0.5, 95% CI 0.32-0.74) [41]. Participants in each group were also randomly assigned to receive six months of isoniazid or not, and this intervention also reduced the incidence of TB. (See 'Optimal timing of ART' below and "Treatment of latent tuberculosis infection in nonpregnant adults with HIV infection".)
TB treatment — Coinfection with tuberculosis (TB) and HIV poses challenging clinical management issues. There are multiple pharmacologic interactions between ART and anti-tuberculosis medications with additive toxicities [64]. Additionally, immune recovery secondary to ART can lead to paradoxical worsening of clinical symptoms in people with tuberculosis; this clinical scenario is referred to as the immune reconstitution inflammatory syndrome (IRIS). (See "Immune reconstitution inflammatory syndrome" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Diagnosis of pulmonary tuberculosis in adults".)
However, data from several trials demonstrate that the mortality reduction observed with early ART (within 2 to 12 weeks after initiating anti-tuberculous therapy) outweighs the potential morbidity of IRIS [65-68]. People with TB meningitis may be an exception to this observation. In one trial of 253 people with HIV and TB meningitis, there was no difference in mortality but an increase in serious adverse events among patients randomly assigned to immediate (within seven days of TB treatment initiation) compared with deferred (after two months) ART initiation [69]. These data and the timing of ART initiation in the setting of TB are discussed in detail elsewhere. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Antiretroviral therapy'.)
Malaria — Since the beginning of the HIV pandemic, malarial infections have doubled in parts of sub-Saharan Africa [70,71] with a higher incidence among those people with low CD4 counts [72]. In one observational cohort of 1371 people with HIV in Uganda, incidence rates of symptomatic malaria infection were higher among people with lower CD4 cell counts (eg, 140, 93, and 57 cases per 1000 person-years of follow-up for CD4 T cell counts <200, 200 to 499, and >500 cells/microL, respectively) [72]. ART initiation in Uganda has been shown to reduce malaria incidence by 64 percent [73]. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)
Cryptococcus — The historically high mortality rates associated with cryptococcal infections in sub-Saharan Africa have also declined with the availability of ART. In a retrospective study of 127 people with cryptococcal meningitis conducted from 1997 to 2005, those who initiated ART were 37 times more likely to survive cryptococcal infection than those who did not [74]. Cohorts in Cape Town and Botswana have demonstrated that ART use was associated with significantly reduced inpatient mortality from cryptococcal meningitis (8 percent versus 21 percent [75]) and reduced mortality at one year (41 percent versus 76 percent [76]) compared with people not yet on therapy at the time of admission.
A paradoxical clinical worsening of symptoms in people with cryptococcal meningitis can occur in the setting of ART initiation and immune recovery, similar to that in mycobacterial disease. Immune reconstitution with cryptococcal disease can be associated with increased intracranial pressure and significant morbidity and mortality if not appropriately monitored [77,78]. The optimal timing of ART initiation for people with cryptococcal meningitis is discussed in greater detail elsewhere. (See "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV".)
The diagnosis and management of cryptococcal infection are also discussed in detail elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention".)
Viral hepatitis — Rates of infection with either hepatitis B or C viruses are high in Africa and Asia. ART use in people with HIV and viral hepatitis raises two main concerns: (a) the effects of viral hepatitis infections on immune recovery; and (b) the risk of drug-associated hepatotoxicity. (See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV" and "Treatment of chronic hepatitis B in patients with HIV" and "Treatment of chronic hepatitis C virus infection in the patient with HIV".)
Despite concerns regarding the potential for negative immunomodulatory effects of viral hepatitis on ART-associated immune reconstitution, data from resource-limited settings have not demonstrated worse outcomes for ART initiation in HBV/HIV-coinfected people. In studies from Thailand, Nigeria, South Africa, and Malawi, people with HBV/HIV coinfection had delayed CD4 gains in early response to ART but attained equivalent immunologic recovery and virologic suppression at 48 to 72 weeks [79-82].
Given the data on hepatotoxicity from resource-rich settings, there is ongoing concern regarding the risk of drug-induced liver injury in HIV/hepatitis-coinfected adults in resource-limited countries [83]. In studies of HIV/HBV-coinfected people on ART from resource-limited settings, hepatotoxicity has been reported more frequently in people with higher HBV DNA viral loads but has not been treatment limiting [79,81,82].
Leishmaniasis — The incidence of leishmania/HIV coinfection is increasing worldwide. Regions that are considered endemic are expanding through India, Eastern Africa, the Middle East, the Mediterranean basin, and South America.
Similar to the negative clinical impact of TB and malaria infection on HIV infection, coinfection with visceral leishmaniasis contributes to accelerated HIV disease progression and increased mortality [84,85]. (See "Visceral leishmaniasis: Clinical manifestations and diagnosis" and "Visceral leishmaniasis: Treatment".)
In a three-year prospective study of 356 people with HIV and leishmaniasis, ART use was associated with decreased risk of relapse, although there was no effect on mortality [85].
Cancer — Since the initial descriptions of AIDS in Africa [86,87], malignancies have been a major cause of morbidity and mortality in individuals with HIV in resource-limited settings. The majority of cancers in the context of HIV infection are linked to oncogenic viral infections, particularly human papilloma virus (HPV), Epstein-Barr virus, and Kaposi sarcoma herpesvirus [88]. The risk is elevated two- to fivefold compared with individuals without HIV [89]. Expansion of ART for individuals with low CD4 cell counts in sub-Saharan Africa has been associated with reduced individual cancer risk for Kaposi sarcoma, the most common cancer in individuals with HIV in the region, but increased population incidence of cervical and other HPV-associated cancers as well as non-Hodgkin lymphoma [90,91]. Initiation of ART prior to the development of immunosuppression, as currently recommended by the WHO, may reduce risk of cancer further [41-43]. The epidemiology and management of HIV-associated cancers are discussed in greater detail elsewhere. (See "HIV infection and malignancy: Epidemiology and pathogenesis" and "HIV infection and malignancy: Management considerations".)
OPTIMAL TIMING OF ART — Initiation of antiretroviral therapy (ART) early in the course of HIV infection rather than waiting for CD4 cell decline reduces severe AIDS and non-AIDS illnesses. Several trials in resource-limited settings have demonstrated the benefit of ART at progressively higher CD4 cell counts.
●A trial in Haiti of over 800 people reported morbidity and mortality benefits of ART initiation at CD4 cell counts of 200 to 350 compared with <200 cells/microL [28].
●In an international trial of over 1700 people, HIV-related clinical events were reduced with ART initiation at CD4 cell counts between 250 and 500 compared with ≤250 cells/microL [92].
●The benefit of even earlier ART initiation was demonstrated in the multicenter TEMPRANO trial in Ivory Coast that included 2056 individuals with HIV who had CD4 cell counts <800 but did not meet the World Health Organization (WHO) criteria for ART initiation (which evolved over the course of the trial, ranging from a CD4 cell threshold of 200 to 500 cells/microL) [41]. Participants were randomly assigned to receive early ART at the time of enrollment or deferred ART, which was initiated once the person met WHO criteria. After 30 months of follow-up, the probability of the composite primary end point of death from any cause, AIDS-defining disease, non–AIDS-defining cancer, or non–AIDS-defining invasive bacterial disease was 6.6 percent with early ART versus 11.4 percent with deferred ART (hazard ratio [HR] 0.56, 95% CI 0.41-0.76). A similar effect was observed among those with a baseline CD4 cell count >500 cells/microL (HR 0.56, 95% CI 0.33-0.94). Importantly, rates of adherence and adverse effects were similar between the study groups.
●Similarly, in the START trial, in which 54 percent of the 4685 participants were from resource-limited settings, immediate ART initiation at CD4 cell counts >500 cells/microL reduced the risk of serious illness or death (HR 0.43, 95% CI 0.30-0.62) compared with delaying ART initiation until CD4 cell count declined to ≤350 cells/microL or an AIDS event occurred [43].
These findings in resource-limited settings have mirrored the evidence from resource-rich settings on the benefit of ART at higher CD4 cell counts. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Rationale for universal treatment'.)
Early ART additionally has the benefit of prevention of transmission. (See 'Prevention of sexual transmission' below and "HIV infection: Risk factors and prevention strategies", section on 'Treatment as prevention'.)
In order to initiate timely ART, WHO recommends offering ART within the first seven days of an HIV diagnosis [7]. Several studies have supported the benefit and feasibility of this approach [93-96]. Nevertheless, the optimal strategy for implementation remains uncertain. As an example, in a randomized trial of 278 newly diagnosed individuals in Lesotho, same day ART initiation with a 30-day supply at home improved health facility linkage to care at three months (69 versus 43 percent) and virologic suppression at 12 months (50 versus 34 percent) compared with routine health facility referral for ART initiation [95]. However, those rates were still unacceptably low, and many trial participants experienced treatment interruption, putting them at risk for drug-resistant HIV. Further study is warranted to identify successful approaches, which may differ by location, patient population, and ART regimen utilized.
IMPACT OF ART ON TRANSMISSION
ART for people with HIV
Prevention of sexual transmission — Reduction in transmission is a key reason for the World Health Organization (WHO) recommendation for antiretroviral therapy (ART) initiation in all individuals with HIV. High plasma HIV RNA concentrations are associated with an increased risk of HIV transmission through sexual intercourse [97]. Achieving undetectable HIV RNA with ART effectively eliminates the risk of transmission of HIV to sexual partners. This concept and the studies demonstrating it are discussed in detail elsewhere. (See "HIV infection: Risk factors and prevention strategies", section on 'Treatment as prevention'.)
Prevention of mother-to-child transmission — The use of ART among pregnant and breastfeeding women with HIV is a critical intervention to reduce the rates of vertical transmission of HIV to their infants. This is discussed in detail elsewhere. (See "Prevention of HIV transmission during breastfeeding in resource-limited settings".)
Pre-exposure prophylaxis — For people at substantial risk of HIV infection, the WHO recommends pre-exposure prophylaxis (PrEP) with an oral regimen containing tenofovir as part of an HIV prevention strategy [6]. The WHO also endorses the dapivirine vaginal ring, if available, as an additional choice for HIV prevention in settings with substantial HIV risk [15]. It defines "substantial risk" as an HIV incidence greater than 3 per 100 person-years, which was the lower range of the incidence among the control groups of the various trials evaluating PrEP.
Despite the need for more data to inform the optimal approach, PrEP with daily tenofovir-emtricitabine appears to be an effective strategy for preventing HIV infection in high-risk uninfected people who are committed to medication adherence and close follow-up. Several trials in various high-risk populations, including men who have sex with men, heterosexual individuals with a partner with HIV, heterosexual individuals in areas of high HIV prevalence, and people who use injection drugs, have demonstrated a reduction in the risk of HIV infection by 48 to 75 percent with daily use of tenofovir-emtricitabine compared with placebo [98-101]. A separate trial in African women that did not show efficacy of tenofovir-emtricitabine in reducing the risk of HIV infection may have been substantially limited by non-adherence [102], but subsequent open-label continuation studies demonstrated improved efficacy [103,104]. Trials of a monthly dapivirine vaginal ring suggested modest reductions in HIV incidence, although these were limited by poor adherence among participants; other analyses suggested greater efficacy among those who were highly adherent to the product [103-106]. These studies are discussed in detail elsewhere. (See "Administration of pre-exposure prophylaxis against HIV infection", section on 'Efficacy of oral pre-exposure prophylaxis'.)
In cost-effectiveness analyses of PrEP, the use of oral or vaginal prophylaxis for prevention of new HIV infections in sub-Saharan Africa has been demonstrated to be cost effective, given the high prevalence of HIV and reported efficacy of PrEP from clinical trials [107-109]. However, PrEP remains costly, and the feasibility of scaling up PrEP in resource-limited settings remains to be determined, especially in light of the ongoing and unmet need for immediate ART for eligible people with HIV.
COST AND COST-EFFECTIVENESS — Despite the increase in costs associated with HIV treatment, the cost-effectiveness of ART in resource-limited settings has been well demonstrated. Mathematical models of ART in Côte d'Ivoire and in India demonstrated substantial life expectancy benefits and favorable cost-effectiveness ratios [110,111]. Modeling studies [112,113] have suggested that earlier initiation of ART is associated with better outcomes in resource-limited settings and is cost-effective. (See 'Ongoing challenges' below.)
ACCESSIBILITY OF LABORATORY TESTING — In resource-rich countries, routine monitoring is standard of care for both drug-related adverse events and ART efficacy (ie, immunologic and virologic responses). In contrast, the optimal strategy for monitoring people on ART in resource-limited settings remains the subject of much debate given the costs of and limited access to CD4 cell count and HIV RNA testing [114-116].
Adverse events — Monitoring for ART-related adverse laboratory events in resource-limited settings is impeded by reduced accessibility to health care providers and limited testing facilities [117]. Cost considerations must also be weighed against the benefit of routine laboratory monitoring in clinical management:
●In a multisite randomized trial in Uganda and Zimbabwe (the DART Trial), 3321 ART-naïve people with HIV and CD4 ≤200 cells/microL were randomly assigned to routine laboratory monitoring after ART initiation (ie, every three months) versus clinically-driven monitoring. Mortality, progression of HIV, and serious adverse events were monitored as endpoints; clinically-driven monitoring was found to be noninferior to routine monitoring for drug toxicity [118]. However, greater disease progression among patients in the clinically-monitored group, and earlier switches to second-line therapy in the laboratory monitored group, suggested an overall beneficial impact of CD4 cell count testing.
●A cohort study of 1800 people on ART in Haiti found that routine laboratory monitoring was cost-effective for assessing anemia before treatment and during therapy with zidovudine; however, routine monitoring of liver or renal function had no impact on overall patient care in this population [119].
ART efficacy — The World Health Organization (WHO) recommends routine CD4 cell count monitoring in people with HIV every 6 to 12 months following diagnosis [6,15]. Additionally, HIV RNA monitoring should be performed and reviewed by 6 months following antiretroviral therapy (ART) initiation and every 12 months thereafter in order to detect treatment failure (defined as persistently detectable viral level >1000 copies/mL when tested on plasma). If HIV RNA testing is not easily available, treatment failure should be indirectly assessed through CD4 cell count and clinical monitoring, with targeted viral load testing used as a confirmatory test when available.
HIV RNA testing has not been associated with a reduction in mortality compared with CD4 cell count or clinical monitoring. However, it can detect treatment failure earlier and with greater accuracy, which is likely to translate into less accumulation of drug resistance and fewer unnecessary switches to second-line regimens. In evaluating its recommendation, the WHO performed a systematic review of studies evaluating the use of CD4 cell count and clinical monitoring for detection of treatment failure, which overall had low sensitivity and poor positive predictive value for identifying virologic failure [6].
Multiple cost-effectiveness analyses evaluating different strategies for monitoring have been published with variable results and conclusions [111,115,120-124]. However, most suggest that CD4 monitoring is cost-effective; HIV RNA and genotype monitoring may be cost-effective depending on the setting [125]. Given that much of the costs associated with treatment failure stem from more costly second-line ART regimens, the cost-effectiveness of these monitoring approaches will likely change as alternate regimens become increasingly available and less expensive [125,126]. (See "Global epidemiology of HIV infection".)
IMPACT OF PROPHYLAXIS AGAINST COINFECTIONS
Trimethoprim-sulfamethoxazole prophylaxis — Trimethoprim-sulfamethoxazole effectively prevents opportunistic infections such as Pneumocystis jirovecii pneumonia and toxoplasmosis, and also effectively reduces the risk of several high-burden bacterial and parasitic infections (eg, Streptococcus pneumoniae, Salmonella species, Shigella species, Isospora, and malaria).
Early randomized trials had demonstrated reductions in morbidity and mortality with trimethoprim-sulfamethoxazole prophylaxis among people with HIV who were not receiving ART, regardless of CD4 count [127-129]. Even in the setting of ART use, trimethoprim-sulfamethoxazole prophylaxis is associated with large reductions in mortality in observational studies from malarial and nonmalarial regions [130,131].
Concerns have been raised regarding the development of trimethoprim-sulfamethoxazole resistance among bacterial and Plasmodium falciparum isolates with the use of chronic prophylaxis for people with HIV. Although some studies have demonstrated increased rates of resistance [132], no data yet suggest an increased rate of clinical failure with trimethoprim-sulfamethoxazole treatment or increased rates of resistance to antimicrobials other than trimethoprim-sulfamethoxazole in communities with high rates of prophylaxis [132-134].
Enhanced prophylaxis — Severe bacterial infection, tuberculosis, and cryptococcal meningitis are major causes of morbidity and mortality among individuals with HIV in resource-limited settings. Antimicrobial prophylaxis to prevent these infections appears to reduce mortality in people with advanced HIV.
In a randomized trial in sub-Saharan Africa (Kenya, Malawi, Uganda, and Zimbabwe), over 1800 adults and children with HIV who were initiating ART and had a CD4 cell count <100 cells/microL were randomly assigned to receive standard trimethoprim-sulfamethoxazole prophylaxis or enhanced prophylaxis with trimethoprim-sulfamethoxazole, isoniazid and pyridoxine for 12 weeks (or longer depending on national guidelines), fluconazole for 12 weeks, azithromycin for 5 days, and a single dose of albendazole [135]. All patients were evaluated for active tuberculosis prior to enrollment and initiated on anti-tuberculous therapy if appropriate. Participants assigned to standard prophylaxis also received isoniazid prophylaxis starting at 12 weeks if indicated based on national guidelines. At 24 weeks, all-cause mortality was lower with enhanced prophylaxis compared with standard prophylaxis (8.9 versus 12.2 percent, hazard ratio 0.73, 95% CI 0.55-0.98), and the benefit was sustained at 48 weeks. Enhanced prophylaxis was also associated with lower rates of the World Health Organization (WHO) stage 3 or 4 clinical events (table 1), new tuberculosis diagnoses, cryptococcal infection, candidiasis, and new hospitalization. Despite the higher pill burden with enhanced prophylaxis, rates of self-reported ART adherence, virologic suppression, and drug-related serious adverse events were comparable across the two groups.
Results from this study, in part, informed WHO recommendations for a package of prophylactic interventions for people with advanced HIV (see 'Prevention of coinfections' above) [7]. These recommendations, however, did not include universal azithromycin or albendazole, because there was insufficient evidence to support the independent benefit of these individual interventions. Furthermore, the recommendations do not support primary prophylaxis with fluconazole (without prior screening for cryptococcal infection and evaluation for meningitis) because of concerns of cost, risk of fluconazole resistance, and potential for fetal toxicity if administered to women of child-bearing potential.
Other studies have suggested a benefit to screening and early treatment for cryptococcal and latent tuberculosis infection, which are included in the WHO-recommended prophylaxis package. These data are discussed elsewhere. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'Screening and treatment of early infection' and "Treatment of latent tuberculosis infection in nonpregnant adults with HIV infection", section on 'Whom to treat'.)
ONGOING CHALLENGES — With the increasing availability of ART, it is essential to determine the most effective features of ART programs in order to target further interventions and to combat the clinical problems unique to developing countries.
HIV diagnostic testing — Delayed HIV diagnosis reduces the survival benefit from ART, and the association between poorer outcomes and advanced immunosuppression is clear [136]. Many people who are diagnosed and enrolled in ART programs die prior to initiating ART or soon thereafter [137,138], emphasizing the need for ongoing efforts for earlier diagnostic testing [139].
Despite current World Health Organization (WHO) guidelines for earlier initiation of treatment, many people are substantially immunosuppressed at the time of diagnosis, and thus are at high risk for early mortality [140]. Substantial improvement has been observed in several high-burden countries [141,142], but improved access to HIV testing and ART initiation remains a global challenge.
Linkage to care and access — Access to care is also affected by community attitudes and stigma towards HIV status and misperceptions regarding HIV risk and treatment [143,144]. Additional barriers include poor coordination of services, reduced educational level, cost of treatment, food insecurity, and transportation [37,138,145-148]. Lower baseline CD4 counts and unemployment have also been associated with poor rates of linkage to care [149]. HIV infection is often diagnosed earlier among females than males because of prenatal testing [150].
Retention in care and loss to follow-up — A critical aspect of HIV treatment is the need for long-term care. Of people who start ART, between 20 and 60 percent are lost to follow-up within one year [144,151,152]. As ART program uptake increases, so do the numbers who fail to return [153].
Loss to follow-up has been associated with poor adherence, older age, advanced immunosuppression, low weight, and pregnancy [37,145,151,154-157]. High rates of death have been reported among those lost to follow-up who could be subsequently tracked [158,159]. Early morbidity related to drug toxicity or opportunistic infections may also contribute to loss to follow-up [160]. Potential interventions include provision of free care, better record-keeping to track patient visits, and the incorporation of ancillary services (eg, peer support groups and outreach services) [145,155,161-163].
Adherence to ART — Antiretroviral therapy (ART) adherence in resource-limited settings is similar or superior to reported data from the United States and Europe, depending on setting and method of measurement [37,143,164].
Reasons for poor adherence in resource-limited settings are frequently related to cost of care [143] and food insecurity [148]. Adherence can also be negatively affected by concerns about stigma within the community, chronic alcohol abuse, and complicated medication regimens [143].
Several studies in various African countries have demonstrated a lower rate of attrition and higher rates of viral suppression if medications are offered free of charge [145,155]. Novel ART delivery models such as adherence clubs and decentralized medication delivery have had varied effects on adherence rates, patient retention and viral suppression [165].
Adherence remains an important predictor of long-term success with ART. In a cohort of 207 people on ART for two years in South Africa, those with poor initial adherence to ART also had a more rapid progression to virologic failure (hazard ratio 2.82, 95% CI 1.19-6.66) [166].
Drug resistance — Due to cost considerations and lack of availability, drug resistance testing is not currently recommended as part of routine HIV management by the WHO and is generally not performed in resource-limited settings. The WHO does recommend performing periodic surveys of HIV drug resistance to better inform national ART policy [167]. (See 'Regimen selection' above.)
High rates of drug resistance have been reported in people starting ART and experiencing virologic failure on ART:
●Drug resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs) is a growing problem in resource-limited settings, in part because of unique challenges due to prior use single-dose nevirapine (and other prevention of mother-to-child transmission (PMTCT) therapies interrupted at birth), use of regimens that may be more vulnerable to resistance, and increased prevalence of HIV subtype C, which is associated with more tenofovir resistance [142,168]. In a systematic review of studies and surveillance reports of antiretroviral resistance in resource-limited settings, the prevalence of genotypes with at least one drug resistance mutation among treatment-naïve individuals increased to 3.7 and 7.4 percent in southern and eastern Africa, respectively, over the five to nine years following rollout of national ART programs [169]. NNRTI resistance mutations (eg, K103N) were most common. Subsequent surveys have indicated continued increases in drug resistance with some countries reporting baseline resistance rates up to 25 percent [170-172].
According to a 2017 WHO report, 6 of 11 countries that conducted national surveys on drug resistance reported >10 percent prevalence of pretreatment NNRTI drug resistance in individuals starting first-line ART, which was associated with prior exposure to antiretroviral agents [167]. Other common mutations include the M184V mutation (conferring resistance to lamivudine and emtricitabine) and K65R (conferring resistance to tenofovir) [173-175].
●Among people treated with an NNRTI-based regimen, the risk of drug resistance in the setting of virologic failure may be considerable [176-181]. In an international study of 1926 patients who experienced treatment failure after tenofovir plus lamivudine or emtricitabine plus an NNRTI, the prevalence of mutations associated with tenofovir resistance ranged from 20 to 60 percent, depending on the geographic regimen, with the highest prevalence in sub-Saharan Africa [180]. The prevalence of mutations associated with NNRTI resistance ranged from 42 to 82 percent. Nevertheless, at least one study suggested that NRTIs retain important efficacy in a second-line regimen despite prior high levels of NRTI resistance. Specifically, in trial from sub-Saharan Africa, 1277 individuals with HIV who had failed treatment with a first-line regimen of an NNRTI plus two NRTIs were randomly assigned to subsequent treatment with a boosted protease inhibitor plus two or three clinician-chosen NRTIs, a boosted protease inhibitor plus raltegravir, or boosted protease inhibitor monotherapy (after three months of combination therapy with raltegravir) [16]. At 96 weeks, viral load <1000 copies/mL was achieved in 88 and 87 percent of the patients in the NRTI and raltegravir groups, respectively, but only 67 percent in the protease inhibitor monotherapy group.
Among people treated with second-line ART, the risk of drug resistance may be different [54,182]. In a study from South Africa of 43 people with HIV and confirmed virologic failure on second-line ART, 67 percent still had wild-type virus. This finding suggests that poor adherence instead of resistance was contributing to failure and may be a result of the different genetic barriers to resistance for protease inhibitors [54]. Additional data are needed to determine the etiologies of ART failure, the patterns of drug resistance to different regimens, and the rates and outcomes of people with resistant virus [176,177]. (See "Interpretation of HIV drug resistance testing".)
Overall, dolutegravir resistance is uncommon, although strategies for evaluating for such resistance in resource-limited settings are uncertain. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Commonly used agents'.)
Test and treat — Given the established efficacy of ART in reducing transmission of HIV among serodiscordant couples [92], there is substantial interest in the evaluation of earlier treatment as a feasible and cost-effective public health strategy to reduce community HIV incidence. One proposal that has sparked interest is that of high-coverage, community voluntary HIV testing with prompt initiation of ART at the time of diagnosis, also known as "test and treat." Mathematical models have predicted a wide range of effectiveness and costs that would result from implementation of such a policy [183-185]. Several large, randomized trials evaluating the test-and-treat strategy have demonstrated modest or no decrease in HIV incidence compared with standard of care [186-189], although this may reflect marked improvements in viral suppression with evolving standard of care. The test-and-treat strategy to prevent HIV infection is discussed in detail elsewhere. (See "HIV infection: Risk factors and prevention strategies", section on 'Test and treat'.)
Costs — Costs of ART and laboratory monitoring remain an ongoing and increasing concern given the greater number of people receiving ART and the need to expand the capacity of treatment programs so that all people can access ART when needed. The increased availability of generic drugs in Guyana, Haiti, Vietnam, and 13 African countries has led to increased procurement of monthly medication packs (from 6 million in 2005 to 22 million in 2008) and to an estimated cost savings of more than 323 million dollars over a four-year period (2005 to 2008) [190]. Cost issues are becoming increasingly important with the demonstration that initiation of therapy earlier in the course of disease results in improved clinical outcomes, highlighting the importance of prioritizing the choice and timing of ART regimens.
Another challenge is to expand effective treatment to people who cannot tolerate first-line regimens because of either toxicity or virologic failure and resistance. Second-line regimens are available in many countries [163], although at considerable increased cost (up to five times that of first-line medications) [191]. Cost-effective algorithms to guide regimen changes for treatment failure remain a subject of debate [126,192].
Concerns regarding funding for international ART programs persist, and debate continues regarding allocation of resources and use of available funds [193,194].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: HIV treatment in nonpregnant adults and adolescents".)
SUMMARY AND RECOMMENDATIONS
●The World Health Organization (WHO) recommends initiation of antiretroviral therapy (ART) in all people with HIV, regardless of CD4 cell count or clinical stage. The use of ART has dramatically reduced both morbidity and mortality for those with HIV/AIDS in resource-limited settings. The benefit of ART is substantial even at high CD4 cell counts. Successful ART for infected individuals also reduces the risk of transmission. (See 'Recommendations from the World Health Organization' above and 'Optimal timing of ART' above and "HIV infection: Risk factors and prevention strategies", section on 'Treatment as prevention'.)
●ART, with secondary immune reconstitution, also decreases the incidence of other prevalent coinfections in patients with HIV, such as malaria, tuberculosis, and cryptococcus. Prophylaxis against these and other coinfections is associated with additional mortality benefit and is recommended for certain populations with HIV (algorithm 1). (See 'Effect of ART on other comorbidities' above and 'Prevention of coinfections' above and 'Impact of prophylaxis against coinfections' above.)
●The WHO recommends pre-exposure prophylaxis with an oral tenofovir-containing regimen for individuals without HIV at substantial risk for infection. Pre-exposure prophylaxis with daily tenofovir-emtricitabine reduces the risk of HIV acquisition, if used with consistency. (See 'Pre-exposure prophylaxis' above and "Administration of pre-exposure prophylaxis against HIV infection".)
●The use of ART among pregnant and breastfeeding females with HIV to prevent transmission of HIV to their infants is discussed in detail elsewhere. (See "Prevention of vertical HIV transmission in resource-limited settings" and "Prevention of HIV transmission during breastfeeding in resource-limited settings".)
●Despite the costs associated with HIV treatment, multiple analyses have demonstrated that initiation of ART is cost effective. (See 'Cost and cost-effectiveness' above.)
●Access to laboratory testing in many resource-limited settings continues to be limited; further investigation of clinical outcomes and cost-effectiveness of different monitoring strategies are needed. (See 'Accessibility of laboratory testing' above.)
●Access to second-line ART for those who have failed first-line is increasingly available. Decreases in drug costs for second-line therapy will enhance this availability. (See 'Costs' above.)
●HIV testing, linkage to care, and retention in care continue to be major factors limiting the success of ART programs in many settings. (See 'Linkage to care and access' above.)
