Retrovir and the dawn of antiretroviral therapy
Retrovir holds a singular place in the history of modern medicine as the first antiretroviral agent approved for the treatment of human immunodeficiency virus infection, marking a transformative moment in the global response to the HIV/AIDS pandemic. The active pharmaceutical ingredient, zidovudine, also known as azidothymidine or AZT, was originally synthesized in 1964 as a potential anticancer agent but was shelved when it failed to demonstrate meaningful antitumor activity. Its rediscovery in the mid-1980s, during the urgent search for compounds that could inhibit HIV replication, led to the demonstration of in vitro activity against the virus and the rapid initiation of clinical trials that would establish its place in medical history.
The clinical development of zidovudine proceeded with unmatched speed, reflecting desperate clinical need created by the growing AIDS epidemic and the absence of any effective therapy for what was then a uniformly fatal disease. The landmark phase 2 clinical trial, initiated in 1986 and terminated early due to clear evidence of benefit, demonstrated that zidovudine reduced mortality and the frequency of opportunistic infections in patients with AIDS or advanced AIDS-related complex. These results, which represented the first definitive demonstration that an antiretroviral agent could alter the natural history of HIV disease, led to the accelerated approval of zidovudine by the United States Food and Drug Administration in March 1987. The regulatory timeline from the first administration of zidovudine to A HIV-infected patient to marketing approval spanned less than two years, a pace that reflected both the severity of the public health emergency and the commitment of regulators, researchers, and the pharmaceutical industry to bringing effective therapy to patients.
The introduction of zidovudine fundamentally altered the therapeutic landscape for HIV infection, transforming the disease from one managed exclusively through treatment and prevention of opportunistic infections to one in which the underlying viral infection could be directly targeted. The early clinical experience with zidovudine, however, revealed the limitations of antiretroviral monotherapy, as the initial clinical benefits proved transient due to the emergence of drug-resistant viral variants and the development of dose-limiting toxicities, particularly bone marrow suppression. These observations catalyzed the search for additional antiretroviral agents targeting different steps in the HIV life cycle, ultimately leading to the development of combination antiretroviral therapy that has made sustained viral suppression achievable for the majority of treated patients.
Molecular mechanism and antiviral pharmacology
Zidovudine exerts its antiviral effects through a mechanism shared by all nucleoside reverse transcriptase inhibitors, involving intracellular conversion to its active triphosphate form and subsequent incorporation into the nascent viral DNA chain by HIV reverse transcriptase. The drug is a thymidine analog in which the 3′-hydroxyl group of the deoxyribose sugar has been replaced by an azido group, a structural modification that preserves the ability of the compound to serve as a substrate for reverse transcriptase while preventing further DNA chain elongation after incorporation. This chain termination mechanism effectively blocks the synthesis of the double-stranded viral DNA intermediate that must be produced for the virus to integrate into the host cell genome and establish productive infection.
The intracellular activation of zidovudine proceeds through a series of phosphorylation reactions catalyzed by cellular kinases, beginning with the conversion of the parent nucleoside to zidovudine monophosphate by thymidine kinase. The addition of a second phosphate group by thymidylate kinase generates zidovudine diphosphate, and the final phosphorylation by nucleoside diphosphate kinase yields the active antiviral metabolite, zidovudine triphosphate. The phosphorylation of zidovudine monophosphate to zidovudine diphosphate by thymidylate kinase is the rate-limiting step in this activation cascade, and the relatively low efficiency of this reaction contributes to the substantial interindividual variability observed in intracellular concentrations of the active triphosphate metabolite.
The selectivity of zidovudine for HIV reverse transcriptase over host cellular DNA polymerases is a critical determinant of its therapeutic index. The active triphosphate form of zidovudine is preferentially incorporated by HIV reverse transcriptase, which lacks the proofreading capability that would allow it to recognize and remove the chain-terminating nucleotide. In contrast, host cellular DNA polymerases, particularly the mitochondrial DNA polymerase gamma, exhibit some susceptibility to inhibition by zidovudine triphosphate, and this off-target inhibition of mitochondrial DNA replication is believed to be responsible for several of the most significant toxicities of the drug, including myopathy, cardiomyopathy, and the lactic acidosis syndrome that complicates long-term therapy.
The pharmacokinetics of zidovudine have been characterized, informing the development of dosing regimens that optimize antiviral activity while minimizing toxicity. Following oral administration, zidovudine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations achieved within 0.5 to 1.5 hours. The absolute oral bioavailability is approximately 60 to 70 percent, reflecting significant first-pass metabolism in the liver. The drug distributes widely throughout the body, including penetration into the cerebrospinal fluid, where concentrations reach approximately 60 percent of simultaneous plasma concentrations. This central nervous system penetration is clinically important, as HIV infection of the brain occurs early in the course of disease and can lead to HIV-associated neurocognitive disorders if not effectively controlled.
Clinical applications and therapeutic evolution
The clinical indications for zidovudine have evolved since its initial approval, reflecting accumulation of clinical trial evidence, the development of newer antiretroviral agents, and the changing demographics of the HIV-infected population. In the current era of antiretroviral therapy, zidovudine is rarely used as a component of initial treatment regimens for treatment-naive patients in resource-rich settings, having been largely supplanted by nucleoside reverse transcriptase inhibitors with more favorable toxicity profiles and dosing schedules. However, zidovudine retains important roles in specific clinical scenarios, including prevention of mother-to-child transmission, post-exposure prophylaxis, and the treatment of patients with limited therapeutic options due to resistance or intolerance to preferred agents.
Prevention of mother-to-child transmission of HIV is the indication for which zidovudine has arguably had the greatest public health impact. The Pediatric AIDS Clinical Trials Group Protocol 076, published in 1994, demonstrated that a three-part zidovudine regimen administered during pregnancy, intrapartum, and to the neonate after delivery reduced the rate of perinatal HIV transmission from approximately 25 percent to 8 percent. This landmark finding transformed the approach to HIV-infected pregnant women and established a standard of care that has been built upon over subsequent decades, with the addition of combination antiretroviral therapy and the refinement of infant prophylaxis strategies. In many resource-limited settings, zidovudine remains a foundation of mother-to-child transmission prevention programs due to its low cost, extensive clinical experience, and availability in formulations suitable for both maternal and neonatal administration.
Post-exposure prophylaxis following occupational or non-occupational exposure to HIV is another clinical indication for which zidovudine has been evaluated and remains a recommended component of many prophylactic regimens. The risk of HIV transmission following percutaneous exposure to HIV-infected blood has been estimated at approximately 0.3 percent, and a case-control study published in 1997 demonstrated that post-exposure prophylaxis with zidovudine reduced this risk by approximately 80 percent. Current recommendations for post-exposure prophylaxis generally include a three-drug regimen initiated as soon as possible, ideally within hours of exposure, and continued for 28 days. Zidovudine in combination with lamivudine, often provided as the fixed-dose combination Combivir, is the nucleoside reverse transcriptase inhibitor backbone of many post-exposure prophylaxis regimens.
The role of zidovudine in the treatment of established HIV infection has diminished in resource-rich settings but remains important in specific patient populations and clinical contexts. Patients who have maintained virological suppression on zidovudine-containing regimens for prolonged periods without significant toxicity, those with viral resistance profiles that preserve susceptibility to zidovudine while conferring resistance to alternative nucleoside reverse transcriptase inhibitors, and those unable to access or tolerate newer antiretroviral agents may continue to derive benefit from zidovudine-based therapy. The decision to initiate or continue zidovudine therapy in the current era should incorporate a comprehensive assessment of treatment history, resistance data, toxicity risk, and patient preferences.
Dosing regimens and therapeutic monitoring
The recommended dosing of Retrovir for the treatment of HIV infection in adults is 300 mg administered orally twice daily, or 200 mg administered three times daily. The total daily dose of 600 mg reflects balance between antiviral efficacy and toxicity established in dose-ranging studies conducted early in the clinical development of zidovudine. Higher doses, including the 1500 mg daily dose used in the original placebo-controlled trial, were associated with greater hematological toxicity without corresponding improvements in antiviral activity or clinical outcomes. The twice-daily dosing option, which has become the standard in contemporary practice, offers the advantage of improved adherence relative to the three-times-daily schedule that was standard during the early years of zidovudine use.
Dosing adjustments for patients with renal impairment are informed by the pharmacokinetics of zidovudine and its glucuronide metabolite. The parent drug is metabolized primarily by hepatic glucuronidation, with the resulting glucuronide metabolite and a portion of unchanged zidovudine excreted by the kidneys. In patients with severe renal impairment, including those with end-stage renal disease receiving hemodialysis, accumulation of the glucuronide metabolite has been observed, though the clinical significance of this accumulation remains uncertain. Current recommendations suggest that patients with creatinine clearance below 15 milliliters per minute, including those receiving hemodialysis, receive a zidovudine dose of 100 mg every six to eight hours, representing approximately 50 to 75 percent of the standard daily dose.
Hepatic impairment affects the metabolism and clearance of zidovudine, as glucuronidation in the liver is the primary route of drug elimination. Patients with cirrhosis or other forms of severe hepatic impairment may exhibit reduced zidovudine clearance and increased systemic exposure, potentially increasing the risk of hematological toxicity. Dose reduction is recommended for patients with severe hepatic impairment, though the specific dose adjustment has not been rigorously defined through clinical studies and should be guided by the development of toxicity and the adequacy of the virological response. Monitoring of hematological parameters and clinical assessment for signs of drug accumulation, including fatigue, pallor, and gastrointestinal symptoms, should be performed with increased frequency in patients with hepatic dysfunction receiving zidovudine.
The laboratory monitoring of patients receiving zidovudine focuses primarily on hematological parameters, as anemia and neutropenia represent the most common dose-limiting toxicities. Complete blood counts with differential should be obtained before the initiation of therapy, at two to four weeks after starting treatment, and at least monthly thereafter during the early months of therapy. Patients who demonstrate stable hematological parameters on a consistent zidovudine dose may be monitored at extended intervals, though any change in clinical status, the development of symptoms suggestive of anemia or infection, or the initiation of concurrent medications with hematological effects should prompt more frequent monitoring. The hemoglobin concentration and absolute neutrophil count serve as the primary parameters guiding dose adjustment decisions, with thresholds for intervention established by clinical trial data and expert consensus.
Adverse effects and clinical toxicity management
Bone marrow suppression is the most clinically significant adverse effect of zidovudine therapy and is the primary dose-limiting toxicity that has influenced the drug’s clinical use and the development of alternative nucleoside reverse transcriptase inhibitors. The anemia associated with zidovudine is typically macrocytic, reflecting effects of the drug on erythroid progenitor cells in the bone marrow, and the development of macrocytosis with an elevated mean corpuscular volume can serve as an indicator of adherence to zidovudine therapy. The severity of anemia is dose-dependent and is more pronounced in patients with advanced HIV disease, low CD4 lymphocyte counts, pre-existing anemia due to HIV infection or opportunistic infections, and concomitant use of other myelosuppressive medications.
Recognized adverse effects of zidovudine therapy include:
- Macrocytic anemia due to suppression of erythroid progenitor cells
- Neutropenia increasing the risk of bacterial and fungal infections
- Gastrointestinal disturbances including nausea, vomiting, and anorexia
- Headache, fatigue, and malaise
- Myopathy and myositis due to mitochondrial toxicity
- Lactic acidosis with hepatic steatosis, a rare but potentially fatal complication
- Lipoatrophy with loss of subcutaneous adipose tissue
- Hyperpigmentation of the nails, skin, and oral mucous membranes
Mitochondrial toxicity resulting from the inhibition of mitochondrial DNA polymerase gamma by zidovudine triphosphate underlies several of the most serious adverse effects of the drug. The depletion of mitochondrial DNA impairs the function of the electron transport chain, reducing cellular energy production and leading to dysfunction in tissues with high metabolic demands. Skeletal muscle is particularly affected, and zidovudine myopathy, characterized by proximal muscle weakness, myalgia, and elevated creatine kinase concentrations, was a significant clinical problem during the era of high-dose zidovudine monotherapy. Muscle biopsy in affected patients reveals ragged red fibers and abnormalities of mitochondrial structure and number, findings that are consistent with mitochondrial dysfunction and that may be partially reversible upon discontinuation of the drug.
Lactic acidosis and severe hepatomegaly with steatosis represent the most severe manifestations of mitochondrial toxicity and are associated with significant mortality. This syndrome, which has been reported with all nucleoside reverse transcriptase inhibitors but is most strongly associated with the thymidine analogs zidovudine and stavudine, presents with nonspecific symptoms including nausea, vomiting, abdominal pain, fatigue, and weight loss, often preceded by a period of several weeks during which these symptoms are attributed to more benign causes. The development of tachypnea, reflecting compensatory respiratory alkalosis in response to metabolic acidosis, may be a late finding that heralds rapid deterioration. Recognition of the prodromal symptoms and prompt discontinuation of nucleoside analog therapy are essential for preventing progression to irreversible cardiovascular collapse.
Lipoatrophy, the loss of subcutaneous adipose tissue involving the face, extremities, and buttocks, has been associated with prolonged zidovudine therapy and is attributed to mitochondrial toxicity in subcutaneous adipocytes. The cosmetic and psychological consequences of lipoatrophy can be significant, contributing to stigmatization, social isolation, and reduced antiretroviral therapy adherence. The recognition of lipoatrophy as a particularly disfiguring adverse effect of thymidine analog therapy has driven the shift toward alternative nucleoside reverse transcriptase inhibitors in treatment guidelines and has stimulated research into strategies for reversing established lipoatrophy, including switch strategies and surgical interventions.
Drug interactions and concomitant medication management
The drug interaction profile of zidovudine encompasses both pharmacokinetic interactions, affecting drug metabolism or elimination, and pharmacodynamic interactions, resulting in additive or antagonistic effects on HIV replication or host toxicity. Understanding these interactions is essential for the safe and effective use of zidovudine as part of combination antiretroviral therapy and in the multiple comorbidities and concurrent medications that characterize the aging HIV-infected population. The management of drug interactions requires vigilance, anticipatory monitoring, and a willingness to adjust doses or select alternative agents when interactions are clinically significant.
Important drug interactions involving zidovudine include:
- Stavudine competition for intracellular phosphorylation precludes combined use
- Ribavirin may antagonize the phosphorylation and antiviral activity of zidovudine
- Probenecid reduces renal clearance of the glucuronide metabolite
- Ganciclovir and valganciclovir potentiate hematological suppression
- Interferon alfa may increase the risk of hepatic decompensation
- Doxorubicin and other chemotherapeutic agents may require dose adjustment
- Methadone may increase zidovudine exposure and toxicity
- Atovaquone and fluconazole may affect zidovudine metabolism
Special populations and pregnancy considerations
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Pregnant women with HIV represent a critically important population for zidovudine therapy, and the drug has been more studied in pregnancy than any other antiretroviral agent. The pharmacokinetics of zidovudine during pregnancy are generally similar to those in non-pregnant adults, and no dose adjustment is required for maternal therapy. The transplacental passage of zidovudine provides fetal exposure that contributes to pre-exposure prophylaxis against intrapartum HIV transmission, one of the mechanisms by which maternal zidovudine therapy reduces perinatal infection risk. The extensive experience with zidovudine in pregnancy, accumulated through clinical trials, observational studies, and the Antiretroviral Pregnancy Registry, has established a favorable safety profile for the fetus when the drug is administered during the second and third trimesters.
Pediatric use of zidovudine encompasses both prophylactic administration to neonates born to HIV-infected mothers and therapeutic administration to infants and children with established HIV infection. Neonatal prophylaxis, a component of the three-part zidovudine regimen for prevention of mother-to-child transmission, is initiated within 6 to 12 hours of birth and continued for six weeks. The neonatal dose, which is weight-based and adjusted as the infant grows, reflects immature hepatic glucuronidation and renal function of the newborn that reduce drug clearance and prolong the elimination half-life relative to older children and adults. Pediatric dosing for the treatment of established HIV infection is calculated based on body surface area or weight and is administered two to four times daily depending on the age and formulation used.
Elderly patients receiving zidovudine present challenges for toxicity management due to age-related declines in renal function, alterations in hepatic drug metabolism, reduced bone marrow reserve, and the presence of comorbid conditions and concurrent medications that may potentiate zidovudine toxicity. While no specific dose adjustments are recommended exclusively on the basis of advanced age, a cautious approach to zidovudine dosing in geriatric patients is warranted, with initiation at the lower end of the dosing range and more gradual dose escalation accompanied by frequent monitoring of hematological parameters and clinical assessment for evidence of drug toxicity. The cumulative toxicity of prolonged antiretroviral therapy, which is increasingly recognized as HIV-infected patients survive into their seventh and eighth decades, may contribute to the accelerated aging phenotype observed in this population.
Renal impairment affects the disposition of zidovudine and its metabolites, and dose adjustment is recommended for patients with creatinine clearance below 15 milliliters per minute. The recommendation to reduce the zidovudine dose in severe renal impairment reflects accumulation of the glucuronide metabolite, which, although lacking significant antiretroviral activity, may contribute to hematological toxicity through intracellular deconjugation back to the parent compound. Hemodialysis removes zidovudine and its metabolites from the circulation, and dosing should be timed to follow dialysis sessions when possible to minimize the period of subtherapeutic drug concentrations. Peritoneal dialysis is less effective at removing zidovudine, and patients receiving this modality of renal replacement therapy may require more conservative dose reductions.
Resistance mechanisms and virological failure
The development of resistance to zidovudine, which was recognized early in the clinical experience with the drug, is a significant limitation of nucleoside reverse transcriptase inhibitor monotherapy and a driver of the evolution toward combination antiretroviral therapy. Zidovudine resistance is mediated by a series of mutations in the reverse transcriptase gene collectively referred to as thymidine analog mutations. These mutations, which include M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E, enhance the ability of reverse transcriptase to excise chain-terminating zidovudine monophosphate from the terminated DNA chain through a phosphorolytic reaction that requires adenosine triphosphate or pyrophosphate as the acceptor molecule. This excision repair mechanism effectively reverses the chain termination that is the basis for zidovudine’s antiviral activity.
The accumulation of thymidine analog mutations occurs in a stepwise fashion under the selective pressure of zidovudine therapy, with each additional mutation conferring incremental increases in the level of resistance. The T215Y/F mutation, which is often the first to emerge, confers partial resistance to zidovudine, while the accumulation of three or more thymidine analog mutations results in high-level resistance that largely eliminates the antiviral contribution of zidovudine to combination therapy. The pace at which resistance mutations accumulate depends on the level of viral replication occurring in the presence of the drug, noting the importance of achieving and maintaining complete viral suppression to prevent the evolution of resistance.
Cross-resistance among nucleoside reverse transcriptase inhibitors is an important consequence of thymidine analog mutation accumulation that has implications for the construction of subsequent antiretroviral regimens. Thymidine analog mutations confer cross-resistance to all thymidine analog nucleoside reverse transcriptase inhibitors, including stavudine, and also reduce susceptibility to other nucleoside reverse transcriptase inhibitors to varying degrees. The presence of multiple thymidine analog mutations, particularly when combined with the M184V mutation conferring lamivudine resistance, compromises the activity of the entire nucleoside reverse transcriptase inhibitor class and necessitates the use of agents from other antiretroviral drug classes to construct effective salvage regimens.
The management of virological failure in patients receiving zidovudine-containing regimens requires prompt recognition, resistance testing while the patient remains on the failing regimen, and a change in therapy guided by the results of resistance testing. Delaying a treatment change in the setting of virological failure allows for the sequential accumulation of resistance mutations, ultimately eliminating future treatment options and compromising the long-term prognosis. Resistance testing should assess both the reverse transcriptase gene for nucleoside reverse transcriptase inhibitor resistance mutations and the protease and integrase genes if these drug classes are being considered as components of the new regimen. The construction of a new regimen for patients with zidovudine resistance should include at least two, and preferably three, fully active agents to which the patient’s virus has no evidence of resistance.
Historical significance and contemporary role
The historical importance of zidovudine in the development of antiretroviral therapy is substantial, as this single compound transformed the treatment paradigm for HIV infection from one of therapeutic nihilism to one of active intervention against the underlying viral disease. The demonstration that a nucleoside analog could inhibit HIV replication and produce clinically meaningful benefits provided proof of principle for the entire class of reverse transcriptase inhibitors and catalyzed the search for additional antiretroviral agents. The lessons learned from the clinical development and post-marketing experience with zidovudine, including the importance of combination therapy, the challenges of drug resistance, and the significance of long-term toxicity profiles, have informed the development and evaluation of every subsequent antiretroviral agent.
In contemporary HIV management, zidovudine continues to serve important roles in specific clinical contexts, even as newer agents with improved toxicity profiles and simpler dosing schedules have become the preferred options for most patients. The extensive evidence base supporting zidovudine for prevention of mother-to-child transmission, the availability of generic formulations at low cost, and the decades of clinical experience with the drug ensure its continued relevance to global HIV treatment and prevention efforts. The fixed-dose combination of zidovudine with lamivudine remains widely available and is listed on the World Health Organization Model List of Essential Medicines, reflecting its importance in resource-limited settings where access to newer antiretroviral agents may be constrained by cost, supply chain limitations, or regulatory considerations.
The legacy of zidovudine extends beyond its direct contributions to HIV therapy to encompass its role in transforming the regulatory framework for drug development in life-threatening diseases. The accelerated approval pathway, which allows for marketing authorization based on surrogate endpoints reasonably likely to predict clinical benefit, was first applied to zidovudine and has since become an important mechanism for expediting patient access to treatments for serious conditions. The patient advocacy movement that arose around access to zidovudine and other antiretroviral agents has influenced drug development policy, pricing, and access across the pharmaceutical industry, with effects extending far beyond HIV to encompass oncology, rare diseases, and other therapeutic areas.
Patient adherence and retention in care
Adherence to zidovudine therapy and the broader antiretroviral regimen is among the most critical determinants of treatment success, as inconsistent medication-taking allows for the resumption of viral replication and the selection of drug-resistant viral variants. The twice-daily dosing schedule of zidovudine, while representing an improvement over the three-times-daily schedule that was historically standard, nevertheless demands a level of consistency and organization that can be challenging for patients facing competing demands from work, family responsibilities, and other health conditions. Adherence interventions, including pillboxes, electronic reminders, directly observed therapy in selected circumstances, and peer support programs, have been evaluated as strategies for improving medication-taking behavior and sustaining long-term adherence.
The identification of barriers to adherence is an essential step in developing individualized strategies to support consistent medication consumption. Common barriers include forgetfulness, busy schedules, travel, the complexity of medication regimens, adverse effects, substance use, mental health disorders, and the stigma associated with HIV that may lead patients to avoid taking medications in the presence of others. Healthcare providers should inquire non-judgmentally about adherence at each clinical encounter, recognizing that patients may overestimate their adherence due to social desirability bias and the desire to avoid disappointing their care team. The use of pharmacy refill records, pill counts, and, when available, electronic adherence monitoring devices, can provide objective data that complements patient self-report.
Retention in care is closely related to adherence and is an additional challenge in the long-term management of HIV infection. Patients who disengage from medical care lose access not only to antiretroviral medications and to the monitoring, preventive services, and management of comorbid conditions that are essential components of comprehensive HIV care. Factors associated with poor retention include younger age, active substance use, mental health disorders, unstable housing, food insecurity, and transportation barriers. Multidisciplinary care teams that include case managers, social workers, and peer navigators can address many of these barriers and have been shown to improve retention in care and clinical outcomes in diverse patient populations.
Pediatric and adolescent hiv management
The management of HIV infection in pediatric patients with zidovudine presents unique challenges and considerations that distinguish this population from adults. Perinatally infected children who have received zidovudine and other antiretroviral agents since infancy face a lifetime of cumulative drug exposure, with concerns about the long-term effects of mitochondrial toxicity, bone marrow suppression, and metabolic complications that may manifest over decades of treatment. The dosing of zidovudine in pediatric patients is weight-based and requires frequent adjustment as children grow, necessitating close coordination between the healthcare team and caregivers to ensure that appropriate doses are administered at each stage of development.
The transition of adolescents with HIV from pediatric to adult care is a particularly vulnerable period during which lapses in care, treatment interruptions, and loss of virological suppression are common. Adolescent patients receiving zidovudine-based therapy require developmentally appropriate education about their disease and its management, gradual assumption of responsibility for medication adherence and healthcare decisions, and structured transition programs that facilitate the transfer of care without gaps in treatment. The involvement of multidisciplinary transition teams that include pediatric and adult providers, social workers, and mental health professionals can improve the continuity of care and the clinical outcomes of young people living with HIV as they navigate the transition to adult healthcare systems.
Adolescents who acquire HIV through sexual transmission or injection drug use present distinct challenges related to the circumstances of their infection, which may include sexual abuse, commercial sex work, or substance use disorders that complicate engagement in care and adherence to therapy. Trauma-informed care approaches that recognize the impact of adverse experiences on health behaviors and outcomes are essential for engaging these vulnerable young people in care and supporting their adherence to zidovudine-based antiretroviral therapy. The integration of mental health services, substance use treatment, and sexual health education into HIV care for adolescents addresses the complex needs of this population and creates a foundation for successful long-term treatment outcomes.